? Intimal hyperplasia (IH), a disease process that accounts for tremendous morbidity and mortality in patients previously treated with angioplasty or vascular reconstruction, is typified by dedifferentiated vascular smooth muscle cells (VSMC) that proliferate, migrate, and are resistant to apoptosis. In preliminary studies, we found that a subtype of protein kinase C, PKC delta (PKCd), profoundly regulates VSMCs in vitro. Specifically, PKCd inhibits SMC proliferation and migration and stimulates SMC apoptosis and differentiation. Moreover, we found that rapamycin, which inhibits restenosis when applied via coronary stents, increases PKCd in cultured VSMCs, suggesting PKCd may be the signal through which rapamycin exerts its profound inhibitory effect. Based on the foregoing, we propose that the potent effects of PKCd on VSMCs might allow this molecule, or a modification, to be used as a specific preventative therapy. We will begin with studies to define the pathways through which PKCd affects VSMC proliferation, apoptosis, and migration and confirm our preliminary data showing downstream regulation through ERK1, p38 and p53.
In specific aim II, we will dissect the PKCd molecule to understand the regulatory mechanism that governs its effects in VSMCs. Specifically; we will evaluate the ability of the catalytic or regulatory domain, as well as phosphorylation of specific tyrosine residues, to regulate PKCd's control over proliferation, migration and apoptosis.
In specific aim III, we will test the role of PKCd through three distinct molecular manipulations in rat and mouse arterial injury models. Finally, in aim IV, we will test the hypothesis, both in vivo and in vitro, that rapamycin affects SMC behavior and IH through induction of PKCd. We anticipate that these studies will further our knowledge of the mechanisms and pathways that contribute to the formation of IH. Moreover, we are encouraged by the profound effect that PKCd has on the SMC dysfunction that accompanies IH and postulate that upregulation of this molecule will be a potential strategy for the prevention of this devastating condition. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL081424-03
Application #
7261885
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Srinivas, Pothur R
Project Start
2005-08-19
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
3
Fiscal Year
2007
Total Cost
$398,236
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Surgery
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Wang, Qiwei; Liu, Zhenjie; Ren, Jun et al. (2015) Receptor-interacting protein kinase 3 contributes to abdominal aortic aneurysms via smooth muscle cell necrosis and inflammation. Circ Res 116:600-11
Bechler, Shane L; Si, Yi; Yu, Yan et al. (2013) Reduction of intimal hyperplasia in injured rat arteries promoted by catheter balloons coated with polyelectrolyte multilayers that contain plasmid DNA encoding PKC?. Biomaterials 34:226-36
Si, Yi; Ren, Jun; Wang, Pu et al. (2012) Protein kinase C-delta mediates adventitial cell migration through regulation of monocyte chemoattractant protein-1 expression in a rat angioplasty model. Arterioscler Thromb Vasc Biol 32:943-54
Lengfeld, Justin; Wang, Qiwei; Zohlman, Andrew et al. (2012) Protein kinase C ýý regulates the release of collagen type I from vascular smooth muscle cells via regulation of Cdc42. Mol Biol Cell 23:1955-63
Saurer, Eric M; Yamanouchi, Dai; Liu, Bo et al. (2011) Delivery of plasmid DNA to vascular tissue in vivo using catheter balloons coated with polyelectrolyte multilayers. Biomaterials 32:610-8
Hong, Hao; Yang, Yunan; Liu, Bo et al. (2010) Imaging of Abdominal Aortic Aneurysm: the present and the future. Curr Vasc Pharmacol 8:808-19
Yamanouchi, Dai; Kato, Kaori; Ryer, Evan J et al. (2010) Protein kinase C delta mediates arterial injury responses through regulation of vascular smooth muscle cell apoptosis. Cardiovasc Res 85:434-43
Kato, Kaori; Yamanouchi, Dai; Esbona, Karla et al. (2009) Caspase-mediated protein kinase C-delta cleavage is necessary for apoptosis of vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 297:H2253-61
Schubl, Sebastian; Tsai, Shirling; Ryer, Evan J et al. (2009) Upregulation of protein kinase cdelta in vascular smooth muscle cells promotes inflammation in abdominal aortic aneurysm. J Surg Res 153:181-7
Zhang, Fan; Kent, K Craig; Yamanouchi, Dai et al. (2009) Anti-receptor for advanced glycation end products therapies as novel treatment for abdominal aortic aneurysm. Ann Surg 250:416-23

Showing the most recent 10 out of 13 publications